GWAS for Sleep Apnea and Endothelial Function Among Mexican Americans

描述(申请人提供)：越来越多的证据表明，一系列非传统的危险因素是高血压、心血管疾病和中风的关键因素。这些因素包括阻塞性睡眠呼吸暂停、内皮功能受损、中心血压高和主动脉僵硬。此外，它们都与2型糖尿病及其并发症有关。这些非传统风险因素的出现提供了关键的生理目标，在这些目标中，了解生物学基础可能会对制定疾病预防战略和/或减缓几种慢性病的进展产生重大影响。众所周知，这些因素中的每一个都有相当大的遗传成分。因此，在全基因组关联研究的背景下，将每种方法的适当测量结合起来，对于阐明那些基因和途径具有巨大的潜力，这些基因和途径的遗传变异调节了危险因素水平的差异，并随后导致疾病。因此，我们建议对来自德克萨斯州斯塔尔县的1200名以前具有特征的墨西哥裔美国人进行非传统风险因素轴的测量，我们将已经从Affymetrix人类基因组范围的SNP阵列6.0平台对他们进行基因分型。这项工作建立在我们28年来对斯塔尔县2型糖尿病及其并发症及其相关疾病的遗传学和流行病学调查经验的基础上。具体地说，我们建议：1)确定基因变异对阻塞性睡眠呼吸暂停、内皮功能受损、中心血压、主动脉僵硬及其特征的贡献；2)确定2型糖尿病和糖尿病前期是否介导基因组与这一非传统危险因素轴的关联；3)通过与包括西班牙裔健康队列在内的其他组织的合作来复制显著的结果；以及4)通过深度重新测序和利用网络理论和进化背景的分析来区分已识别基因的原因多态和简单的连锁不平衡。在拉美裔人群中，关于这一危险因素轴的流行病学数据一般很少。此外，对这些危险因素在任何人群中的全基因组关联研究还没有进行到任何重大程度。事实证明，这类研究在识别之前未涉及慢性病风险的基因方面非常有效，可能会为干预开辟新的途径。我们预计，我们提议的研究将对这组非传统风险因素进行同样的研究。考虑到它们在生理上的相互关联性，以及它们与一系列疾病的一致联系，它们特别有吸引力，这些疾病对大多数人口承担的发病率和死亡负担负有最大责任。

DESCRIPTION (provided by applicant): Accumulating evidence is establishing a series of less traditional risk factors as being critical for hypertension, cardiovascular disease and stroke. These factors include obstructive sleep apnea, impaired endothelial function, high central blood pressure and aortic stiffness. Furthermore, they are each associated with type 2 diabetes and its complications. The emergence of these non-traditional risk factors provides key physiologic targets where understanding the biological underpinnings could have substantial impact on developing strategies for disease prevention and/or slowing the progression of several chronic conditions. Each of these factors is known to have a substantial genetic component. Consequently, coupling appropriate measures of each in the context of a genome-wide association study has immense potential for elucidating those genes and pathways whose genetic variation mediates differences in risk factor levels and subsequently disease. Accordingly, we propose to measure this axis of non-traditional risk factors in 1,200 previously characterized Mexican Americans from Starr County, Texas, for whom we will already have genotyping from the Affymetrix Human Genome-Wide SNP Array 6.0 platform. This work builds on our 28 years of experience investigating the genetics and epidemiology of type 2 diabetes, its complications, and related conditions in Starr County. Specifically, we propose: 1) to determine the contribution of genetic variation to obstructive sleep apnea, impaired endothelial function, central blood pressure, aortic stiffness and their profile; 2) to determine whether type 2 diabetes and pre-diabetes mediate genomic associations with this axis of non-traditional risk factors; 3) to replicate significant results through collaboration with other groups including the Hispanic Health Cohort; and 4) to distinguish causal polymorphisms from those simply in linkage disequilibrium for identified genes through deep re-sequencing and analyses that exploit network theory and evolutionary contexts. There is a paucity of epidemiologic data for this axis of risk factors in the Hispanic population in general. Furthermore, genome-wide association studies of these risk factors in any population have not yet been conducted to any significant extent. Such studies have proven to be remarkably effective in identifying genes not previously implicated in chronic disease risk potentially opening new pathways for intervention. We expect our proposed study to do the same for this set of non-traditional risk factors. They are particularly attractive given their physiologic interrelatedness and their consistent associations with the constellation of diseases most responsible for the morbidity and mortality burden borne by most populations.